Fetal alcohol syndrome and related disorders are the leading known cause of mental retardation. Understanding the neuropathology of prenatal alcohol exposure is critical. Methods for preventing alcohol associated brain damage in the fetus are lacking due to limited understanding of alcohol disruption of neuronal development. To address this gap in knowledge, we are investigating the role of neuronal-glial interactions in alcohol-mediated neurotoxicity during development. Microglia are uniquely important because they provide neuronal protection or, with pathologic activation, mediate neuronal death. Using co-cultures of cerebellar granule cells and microglia, we have found that microglia effectively protect neurons against alcohol toxicity. Our studies using an in vivo neonatal rat model reveal that a single alcohol dose produces almost 40% microglial loss in the developing cerebellum, and the surviving cells appear to be pathologically activated. Studies in culture suggest that alcohol-induced microglial loss is occurring by apoptosis. Thus, alcohol depletion of the microglial population may disrupt microglial-derived neuroprotection in the developing brain. Interestingly, our studies also reveal that alcohol reduces levels of the PPARgamma protein and, further, pharmacologic activation of PPARy can reduce alcohol cytotoxicity in microglia and neurons. To further these findings, we propose to investigate the overall hypothesis that alcohol disruption of microglial-neuronal interactions includes induction of microglial apoptosis, microglial activation, and suppression of microglial-derived neuroprotection. Complementary in vivo and in vitro models will be used to test this hypothesis. The specific aims of this proposal are to: 1. Determine whether alcohol-induced microglial cell loss in the developing cerebellum occurs by apoptosis. 2. Determine whether alcohol induces activation of the surviving microglial population. 3. Establish whether the deleterious effects of alcohol on developing microglia disrupt interactions between neurons and microglia. 4. Establish whether alcohol induced loss of neurons and microglia in the cerebellum involves suppression of PPARgamma, signaling and can be prevented by PPARgamma activation. Results of this study will provide better understanding of alcohol interference with the relationship between microglia and neurons. Application of this knowledge may provide new therapeutic strategies for intervention in the neuropathology caused by prenatal alcohol exposure.